Restoration by VIP of the Carbachol-Stimulated Cl⁻ Secretion in TTX-Treated Guinea Pig Distal Colon

Abstract

To determine if vasoactive intestinal peptide (VIP) restores neural activity from tetrodotoxin (TTX) blockade, we studied the effects of VIP and related agents on carbachol (Cch)-induced Cl⁻ secretion in control isolated guinea pig distal colon and in that treated with TTX. The short circuit current (I_sc) increased dose-dependently after serosal application of Cch (10⁻⁶–2 × 10⁻⁵ M) and VIP (5 × 10⁻⁹–10⁻⁷ M). But no additive or synergistic increase in I_sc was observed. Cch- and VIP-induced I_sc was completely abolished by serosal application of TTX (10⁻⁶ M). However, serosal, but not mucosal, application of VIP (10⁻⁷ M) and 8-bromo-cAMP (10⁻³ M) restored the Cch-stimulated, TTX-inhibited I_sc by 113% and 75.8%, respectively. Furthermore, mucosal and serosal application of forskolin (adenylate cyclase activator) restored the I_sc by 43.9% and 65.3%, respectively. The restored I_sc was completely abolished by atropine (muscarinic receptor antagonist). These results suggest that VIP may restore the cholinergic activity by increasing the level of intracellular cAMP, and that cholinergic neuron is likely to be responsible for regulation of Cl– secretion at neuroepithelial junctions. The exact mechanism of VIP’s effect on the TTX-inhibited epithelial Cl⁻ secretion, and its possible usefulness in the treatment of TTX-induced pathophysiological condition, remain to be determined.